Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status

Jeremy M. Rosenblum, N. A. Ari Wijetunga, Melissa J. Fazzari, Mark Krailo, Donald A. Barkauskas, Richard Gorlick, John M. Greally

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Osteosarcoma is the most common primary malignant bone tumor in children. Validated biological markers for disease prognosis available at diagnosis are lacking. No genome-wide DNA methylation studies linked to clinical outcomes have been reported in osteosarcoma to the best of our knowledge. To address this, we tested the methylome at over 1.1 million loci in 15 osteosarcoma biopsy samples obtained prior to the initiation of therapy and correlated these molecular data with disease outcomes. At more than 17% of the tested loci, samples obtained from patients who experienced disease relapse were more methylated than those from patients who did not have recurrence while patients who did not experience disease relapse had more DNA methylation at fewer than 1%. In samples from patients who went on to have recurrent disease, increased DNA methylation was found at gene bodies, intergenic regions and empirically-annotated candidate enhancers, whereas candidate gene promoters were unusual for a more balanced distribution of increased and decreased DNA methylation with 6.6% of gene promoter loci being more methylated and 2% of promoter loci being less methylated in patients with disease relapse. A locus at the TLR4 gene demonstrates one of strongest associations between DNA methylation and 5 y event-free survival (P-value = 1.7 × 10-6), with empirical annotation of this locus showing promoter characteristics. Our data indicate that DNA methylation information has the potential to be predictive of outcome in pediatric osteosarcoma, and that both promoters and non-promoter loci are potentially informative in DNA methylation studies.

Original languageEnglish (US)
Pages (from-to)31-39
Number of pages9
JournalEpigenetics
Volume10
Issue number1
DOIs
StatePublished - Jan 23 2015

Keywords

  • DNA methylation
  • Epigenetics
  • Osteosarcoma
  • Relapse

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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